HIV-Specific Probabilistic Models of Protein Evolution

University of Oxford, United Kingdom
PLoS ONE (Impact Factor: 3.23). 02/2007; 2(6):e503. DOI: 10.1371/journal.pone.0000503
Source: PubMed


Comparative sequence analyses, including such fundamental bioinformatics techniques as similarity searching, sequence alignment and phylogenetic inference, have become a mainstay for researchers studying type 1 Human Immunodeficiency Virus (HIV-1) genome structure and evolution. Implicit in comparative analyses is an underlying model of evolution, and the chosen model can significantly affect the results. In general, evolutionary models describe the probabilities of replacing one amino acid character with another over a period of time. Most widely used evolutionary models for protein sequences have been derived from curated alignments of hundreds of proteins, usually based on mammalian genomes. It is unclear to what extent these empirical models are generalizable to a very different organism, such as HIV-1-the most extensively sequenced organism in existence. We developed a maximum likelihood model fitting procedure to a collection of HIV-1 alignments sampled from different viral genes, and inferred two empirical substitution models, suitable for describing between-and within-host evolution. Our procedure pools the information from multiple sequence alignments, and provided software implementation can be run efficiently in parallel on a computer cluster. We describe how the inferred substitution models can be used to generate scoring matrices suitable for alignment and similarity searches. Our models had a consistently superior fit relative to the best existing models and to parameter-rich data-driven models when benchmarked on independent HIV-1 alignments, demonstrating evolutionary biases in amino-acid substitution that are unique to HIV, and that are not captured by the existing models. The scoring matrices derived from the models showed a marked difference from common amino-acid scoring matrices. The use of an appropriate evolutionary model recovered a known viral transmission history, whereas a poorly chosen model introduced phylogenetic error. We argue that our model derivation procedure is immediately applicable to other organisms with extensive sequence data available, such as Hepatitis C and Influenza A viruses.

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Available from: Laura Heath
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    • "Perhaps this could be derived from the application of not enough realistic models of HIV-1 evolution as suggested in [17]; see also [20]. Knowledge on HIV-1 molecular evolution can also be used to develop realistic models of evolution [21] [22] that can be applied for additional purposes such as the prediction of resistance mutations [23] or the evolutionary reply of the viral population, genotypic resistance testing [24] [25]. "
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    • "All amino acid evolutionary rate models available in ProtTest were examined, as were the parameters " +I," " +G," and " +F " . (Dayhoff et al. 1978), JTT (Jones et al. 1992), WAG (Whelan and Goldman 2001), mtREV (Adachi and Hasegawa 1996), MtMam (Cao et al. 1994), VT (Müller and Vingron 2000), CpREV (Adachi et al. 2000), RtREV (Dimmic et al. 2002), MtArt (Abascal et al. 2007), HIVb/HIVw (Nickle et al. 2007), LG (Le and Gascuel 2008), and Blosum62 (Henikoff 1992). Ideally, we would optimize tree topology, branch lengths, and parameters of the model for each model investigated. "
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    • "Since CD4 counts and information on viral load were unavailable for the early samples, we employed computational approaches to infer diversity changes and to detect positive selection acting on the env gene. In particular, we are interested in whether positive selection pressure differs between the early and recent samples and between within-host and between-host evolution [16], [17]. We are also interested in detecting sites in the env gene targeted by the human immune system. "
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